DESCRIPTION: The studies proposed aim to identify mechanisms leading to accelerated atherosclerotic lesion initiation in the presence of hyperglycemia. We will focus on endothelial cells and macrophages-the two most important cell types in lesion initiation. The experiments will be carried out in isolated mouse endothelial cells and macrophages, and in a transgenic LDL receptor-deficient mouse model in which type 1 diabetes can be induced by a virus (the LDLR-/-;GP mouse). Based on preliminary experiments, we hypothesize that the main atherogenic effects of hyperglycemia are dependent on increased formation of fatty acyl-CoAs, through increased activity of long chain acyl-CoA synthetase 1 (AcsM). We propose to directly test the contribution acyl-CoA synthesis in the effects of glucose and diabetes on lesion initiation by targeted modulation of expression levels of Acsl1 in endothelial cells and macrophages. The goal is to address the following three questions: 1) Is acyl-CoA synthesis of central importance in glucose-stimulated production of inflammatory molecules by cultured endothelial cells and macrophages?; 2) Does increased acyl-CoA synthesis in macrophages mimic the effects of diabetes on inflammatory mediators and lesion initiation in LDLR-/-;GP mice?; 3) Does inhibition of acyl-CoA synthesis in endothelial cells or macrophages retard lesion initiation in our mouse model of accelerated diabetic atherosclerosis? These studies will increase our understanding of the molecular mechanisms involved in diabetes-accelerated lesion initiation under hyperglycemic conditions. Identification of such mechanisms might be used to develop drugs to target cardiovascular complications of type 1 diabetes. [unreadable] [unreadable] [unreadable]